The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.
More particularly this invention provides orthosulfonamido aryl hydroxamine acids as matrix metalloproteinase inhibitors processes for their preparation and pharmaceutical compositions containing them.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, J. F., Jr. FASEB J. 1991, 5, 2145; Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A. Crit. Rev. Oral Biol. Med. 1993, 4, 197; Cawston, T. E. Pharmacol. Ther. 1996, 70, 163; Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1]. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D. S.; Pelletier, J.-P. In Arthritis and Allied Conditions; McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D. Sem. Arthritis Rheum. 1991, 20, 2; Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323].
It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which may lead to tumor metastasis [Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Himelstein, B. P.; Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.; Muschel, R. J. Invasion Metast. 1994-95, 14, 246; Nuovo, G. J.; MacConnell, P. B.; Simsir, A.; Valea, F.; French, D. L. Cancer Res. 1995, 55, 267-275; Walther, M. M.; Levy, A.; Hurley, K.; Venzon, D.; Linehen, W. M.; Stetler-Stevenson, W. J. Urol. 1995, 153 (Suppl. 4), 403A; Tokuraku, M; Sato, H.; Murakami, S.; Okada, Y.; Watanabe, Y.; Seiki, M. Int. J. Cancer, 1995, 64, 355; Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R. J. Proc. Am. Assoc. Cancer Res. Ann. Meet. 1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y. Am. J. Pathol. 1996, 148, 611; Gress, T. M.; Mueller-Pillasch, F.; Lerch, M. M.; Friess, H.; Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407; Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.; Okada, Y. Virchows Arch., 1994, 424, 547-552.]. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H. C; Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis [Dollery, C. M.; McEwan, J. R.; Henney, A. M. Circ. Res. 1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H. J.; Clowes, A. W. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 28; Lee, R. T.; Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 1070.]. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren""s syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
The hypothesis that MMPs are important mediators of the tissue destruction that occurs in arthritis has long been considered, since it was first recognized that these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F., Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.; Woessner, J. F., Jr., Arthritis Rheum. 1983, 26, 63.], and continues to develop as new MMPs are identified. For example, collagenase-3 (MMP-13) was cloned from breast cancer cells in 1994, and the first report that it could be involved in arthritis appeared in 1995 [Freiji, J. M.; Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C. R.; Sandy, J. D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, Fla. Feb. 13-16, 1995.]. Evidence is accumulating that implicates MMP-13 in the pathogenesis of arthritis. A major structural component of articular cartilage, type II collagen, is the preferred substrate for MMP-13 and this enzyme is significantly more efficient at cleaving type II collagen than the other collagenases [Knauper, V.; Lopez-Otin, C.; Smith, B.; Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell, P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S. A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J. E. J. Clin. Invest. 1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268; Shlopov, B. V.; Mainardi, C. L.; Hasty, K. A. Arthritis Rheum. 1995, 38 (Suppl. 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. J. Clin. Invest. 1996, 97, 2011]. Potent inhibitors of MMPs were described over 10 years ago, but the poor bioavailability of these early peptidic, substrate mimetic MMP inhibitors precluded their evaluation in animal models of arthritis. More bioavailable, non-peptidic MMP inhibitors may be preferred for the treatment of diseases mediated by MMPs.
It is expected that small molecule inhibitors of gelatinase therefore have the potential for treating a variety of disease states. While a variety of MMP inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic or peptide-like compounds that may have bioavailability and pharmacokinetic problems that would limit their clinical effectiveness. Low molecular weight, potent, long-acting, orally bioavailable inhibitors of gelatinases and collagenases are therefore highly desirable for the potential chronic treatment of the above mentioned disease states. Several non-peptide, sulfur-containing hydroxamic acids have recently been disclosed and are listed below.
U.S. Pat. Nos. 5,455,258, 5,506,242 and 5,552,419, as well as European patent application EP606,046A1 and WIPO international publications WO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997),40, 2525. Additional publications disclosing sulfonamide based MMP inhibitors which are variants of the sulfonamide-hydroxamate shown below, or the analogous sulfonamidecarboxylates, are European patent application EP-757984-A1 and WIPO international publications WO95/35275, WO95/35276, WO96/27583, WO97/19068 and WO97/27174. 
Publications disclosing xcex2-sulfonamide-hydroxamate MMP inhibitor analogs of CGS 27023A in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen, as shown below, include WIPO international publications WO96/33172 and WO97/20824. 
The German patent application DE19,542,189-A1 discloses additional examples of cylic sulfonamides as MMP inhibitors. In this case the sulfonamide-containing ring is fused to a phenyl ring to form an isoquinoline. 
Analogs of the sulfonamide-hydroxamate MMP inhibitors in which the sulfonamide nitrogen has been replaced by a carbon atom, as shown in the general structure below, are European patent application EP-780386-A1 and WIPO international publication WO97/24117. 
Certain ortho-sulfonamido aryl hydroxamic acids are described in U.S. Pat. No. 5,929,097, WO9816514 and WO9816520.
The MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by formula I 
where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of group A where:
A is aryl, heteroaryl or heteroaryl fused to a phenyl ring;
Z is aryl, heteroaryl, or heteroaryl fused to a phenyl;
E and G are independently CH2, NR5, or O, or S or a bond:
Y is cycloalkyl, cycloheteroalkyl, xe2x80x94C1-C5-perfluoroalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, alkylaryl, or heteroaryl;
J is aryl, heteroaryl, heteroaryl fused to a phenyl, cycloalkyl, cycloheteroalkyl, xe2x80x94C1-C5-perfluoroalkyl, alkyl, alkenyl, or alkynyl;
R5 and R6 are independently H, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, xe2x80x94C1-C4-perfluoroalkyl, alkyl, alkenyl, or alkynyl;
R7 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or 3-6 membered cycloheteroalkyl; or
R7CH2xe2x80x94Nxe2x80x94Axe2x80x94 can form a non-aromatic 1,2-benzo-fused 7-10 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
L is xe2x80x94C(O)xe2x80x94, S(O)y, xe2x80x94NR5C(O)NR6xe2x80x94, xe2x80x94NR5C(O)Oxe2x80x94, xe2x80x94OC(O)NR5xe2x80x94, xe2x80x94SC(O)xe2x80x94, xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR5C(O)xe2x80x94, xe2x80x94C(O)NR5xe2x80x94, xe2x80x94SC(O)NR5, xe2x80x94NR5C(O)Sxe2x80x94, xe2x80x94OC(O)Oxe2x80x94;
y is 1 or 2;
and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
Preferred compounds of the invention are those wherein:
A is aryl, heteroaryl or heteroaryl fused to a phenyl ring optionally substituted by one or more of R1, R2, R3 and R4 the same or different;
Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, optionally substituted by one or more of R10, R11, R12and R13 the same or different;
R1, R2, R3, R4, R10, R11, R12, R13, R14, R15, R16, R17, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30 and R31 are independently xe2x80x94H, xe2x80x94COR5, xe2x80x94F, xe2x80x94Br, xe2x80x94Cl, xe2x80x94I, C(O)NR5OR6, xe2x80x94CN, xe2x80x94OR5, xe2x80x94C1-C4-perfluoroalkyl, xe2x80x94S(O)xR5, xe2x80x94OPO(OR5)OR6, xe2x80x94PO(OR6)R5, xe2x80x94OC(O)NR5R6, xe2x80x94COOR5, xe2x80x94CONR5R6, xe2x80x94SO3H, xe2x80x94NR5R6, xe2x80x94NR5COR6, xe2x80x94NR5COOR6, xe2x80x94SO2NR5R6, xe2x80x94NO2, xe2x80x94N(R5)SO2R6, xe2x80x94NR5CONR5R6NR5C(xe2x95x90NR6)NR5R6, 3-6 membered cycloheteroalkyl, aryl, heteroaryl, biphenyl, xe2x80x94SO2NHCOR18 , xe2x80x94CONHSO2R18 , -tetrazol-5-yl, xe2x80x94SO2NHCN, xe2x80x94SO2NHCONR5R6 or straight chain or branched xe2x80x94C1-C6 alkyl, xe2x80x94C2-C6-alkenyl, or xe2x80x94C2-C6-alkynyl, or xe2x80x94C3-C6-cycloalkyl, each optionally substituted with xe2x80x94COR5, xe2x80x94CN, xe2x80x94C2-C6 alkenyl, xe2x80x94C2-C6 alkynyl, xe2x80x94OR5, xe2x80x94C1-C4-perfluoroalkyl, xe2x80x94S(O)xR5, xe2x80x94OC(O)NR5R6, xe2x80x94COOR5, xe2x80x94CONR5R6, xe2x80x94SO3H, xe2x80x94NR5R6, xe2x80x94NR5COR6, xe2x80x94NR5COOR6, xe2x80x94SO2NR5R6, xe2x80x94NO2, xe2x80x94N(R5)SO2R6, xe2x80x94NR5CONR5R6, xe2x80x94C3-C6cycloalkyl, 3-6 R20, R21,membered cycloheteroalkyl, aryl, heteroaryl, biphenyl, xe2x80x94SO2NHCOR18, xe2x80x94CONHSO2R18; xe2x80x94PO(OR5)OR6, xe2x80x94PO(OR6)R5, -tetrazol-5-yl, C(O)NR5OR6, xe2x80x94NR5C(xe2x95x90NR6)NR5R6, xe2x80x94SO2NHCONR5R6 or xe2x80x94SO2NHCN; or
when any of R1 and R2, or R10 and R11 or R14 and R15 are on adjacent carbons of A or J or Z respectively, then each pair of R1 and R2, or R10 and R11 or R14 and R15 together with the carbons to which they are attached can form a 5 to 7 membered saturated or unsaturated heterocyclic ring, a 5-6 membered heteroaryl ring, or a 5 to 7 membered saturated or unsaturated carbocyclic ring;
x is 0-2;
E and G are independently CH2, NR5, or O, or S or a bond:
Y is xe2x80x94C3-C6-cycloalkyl, xe2x80x94C3-C6-cycloheteroalkyl, xe2x80x94C1-C5-perfluoroalkyl, straight chain or branched xe2x80x94C1-C6 alkyl, straight or branched chain C2-C6-alkenyl, or straight or branched chain C2-C6-alkynyl or heteroalkyl, alkylaryl, heteroaryl optionally substituted with R20, R21 R22, and R23;
J is aryl, heteroaryl, or heteroaryl fused to a phenyl; optionally substituted with R14, R15, R16, and R17 or xe2x80x94C3-C6-cycloalkyl, xe2x80x94C3-C6-cycloheteroalkyl, xe2x80x94C1-C5-perfluoroalkyl, straight chain or branched xe2x80x94C1-C6 alkyl, straight or branched chain xe2x80x94C2C6-alkenyl, or straight or branched chain C2-C6-alkynyl;
R5 and R6 are independently H, aryl, heteroaryl, xe2x80x94C3-C6-cycloalkyl, xe2x80x94C3-C6cycloheteroalkyl, xe2x80x94C1-C4-perfluoroalkyl, or straight chain or branched xe2x80x94C1-C6 alkyl, xe2x80x94C2-C6-alkenyl, or xe2x80x94C2-C6-alkynyl, each optionally substituted with xe2x80x94OH, xe2x80x94COR8, xe2x80x94CN, xe2x80x94C(O)NR8OR9, xe2x80x94C2-C6-alkenyl, xe2x80x94C2-C6-alkynyl, xe2x80x94OR8, xe2x80x94C1-C4-perfluoroalkyl, xe2x80x94S(O)xR8, xe2x80x94OPO(OR8)OR9, xe2x80x94PO(OR8)R9, xe2x80x94OC(O)NR8R9, xe2x80x94COOR8, xe2x80x94CONR8R9, xe2x80x94SO3H, xe2x80x94NR8R9, xe2x80x94NCOR8R9, xe2x80x94NR8COOR9, xe2x80x94SO2NR8R9, xe2x80x94NO2, xe2x80x94N(R8)SO2R9, xe2x80x94NR8CONR8R9, xe2x80x94C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, aryl, heteroaryl, xe2x80x94SO2NHCOR19, xe2x80x94CONHSO2R19, -tetrazol-5-yl, NR8C(xe2x95x90NR9)NR8R9, xe2x80x94SO2NHCONR8R9, or xe2x80x94SO2NHCN;
R7 is hydrogen, straight chain or branched xe2x80x94C1-C6-alkyl, xe2x80x94C2-C6-alkenyl, or xe2x80x94C2-C6-alkynyl each optionally substituted with xe2x80x94OH, xe2x80x94COR5, xe2x80x94CN, xe2x80x94C2-C6-alkenyl, xe2x80x94C2-C6-alkynyl, xe2x80x94OR5, xe2x80x94C1-C4-perfluoroalkyl, xe2x80x94S(O)xR5, OPO(OR5)OR6, xe2x80x94PO(OR5)R6, xe2x80x94OC(O)NR5R6, xe2x80x94COOR5, xe2x80x94CONR5R6, xe2x80x94SO3H, xe2x80x94NR5R6, xe2x80x94NR5COR6, xe2x80x94NR5COOR6, xe2x80x94SO2NR5R6, xe2x80x94NO2, xe2x80x94N(R5)SO2R6, xe2x80x94NR5CONR5R6, xe2x80x94C3xe2x80x94C6 cycloalkyl, xe2x80x94C3-C6-cycloheteroalkyl, -aryl, heteroaryl, xe2x80x94SO2NHCOR32, xe2x80x94CONHSO2R32, -tetrazol-5-yl, xe2x80x94NR5C(xe2x95x90NR6)NR5R6, xe2x80x94C(O)NR5OR6, xe2x80x94SO2NHCONR5R6 or xe2x80x94SO2NHCN;
or R7 is phenyl or naphthyl, optionally substituted by R24, R25, R26 and R27 or a 5 to 6 membered heteroaryl group optionally substituted by R28, R29, R30 and R31; or
R7 is C3-C6 cycloalkyl or 3-6 membered cycloheteroalkyl; or
R7CH2xe2x80x94Nxe2x80x94Axe2x80x94 (where R7 is bonded to A) can form a non-aromatic 1,2-benzo-fused 7-10 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring such as for example: 
R8 and R9 are independently H, aryl or heteroaryl, xe2x80x94C3-C7 cycloalkyl or 3 to 6 membered cycloheteroalkyl, xe2x80x94C1-C4-perfluoroalkyl, straight chain or branched xe2x80x94C1-C6-alkyl, xe2x80x94C2-C6-alkenyl, or xe2x80x94C2-C6-alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, xe2x80x94C1-C4-perfluoroalkyl, amino, mono- and di-C1-C6-alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-C1-C6-alkylcarbamoyl;
R18 and R32 are independently aryl, heteroaryl, xe2x80x94C3-C6-cycloalkyl, xe2x80x94C3-C6-cycloheteroalkyl, xe2x80x94C1-C4-perfluoroalkyl, or straight chain or branched xe2x80x94C1-C6 alkyl, C2-C6-alkenyl, or xe2x80x94C2-C6-alkynyl, each optionally substituted with xe2x80x94OH, xe2x80x94COR8, xe2x80x94CN, xe2x80x94C(O)NR8OR9, xe2x80x94C2-C6-alkenyl, xe2x80x94C2-C6-alkynyl, xe2x80x94OR8, xe2x80x94C1-C4-perfluoroalkyl, xe2x80x94S(O)xR 8, xe2x80x94OPO(OR8)OR9, xe2x80x94PO(OR8)R9, xe2x80x94OC(O)NR8R9, xe2x80x94COOR8, xe2x80x94CONR8R9, xe2x80x94SO3H, xe2x80x94NR8R9, xe2x80x94NCOR8R9, xe2x80x94NR8COOR9, xe2x80x94SO2NR8R9, xe2x80x94NO2, xe2x80x94N(R8)SO2R9, xe2x80x94NR8CONR8R9, xe2x80x94C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, aryl, heteroaryl, xe2x80x94SO2NHCOR19, xe2x80x94CONHSO2R19, -tetrazol-5-yl, NR8C(xe2x95x90NR9)NR8R9, xe2x80x94SO2NHCONR8R9, or xe2x80x94SO2NHCN;
R19 is aryl or heteroaryl, xe2x80x94C3-C7cycloalkyl or 3 to 6 membered cycloheteroalkyl, xe2x80x94C1-C4-perfluoroalkyl, straight chain or branched xe2x80x94C1-C6-alkyl, xe2x80x94C2C6-alkenyl, or xe2x80x94C2-C6-alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, xe2x80x94C1-C4-perfluoroalkyl, amino, mono- and di-C1-C6-alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-C1-C6-alkylcarbamoyl;
L is xe2x80x94C(O)xe2x80x94, S(O)y, xe2x80x94NR5C(O)NR6xe2x80x94, xe2x80x94NR5C(O)Oxe2x80x94, xe2x80x94OC(O)NR5xe2x80x94, xe2x80x94SC(O)xe2x80x94, xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR5C(O)xe2x80x94, xe2x80x94C(O)NR5xe2x80x94, xe2x80x94SC(O)NR5, xe2x80x94NR5C(O)Sxe2x80x94, xe2x80x94OC(O)Oxe2x80x94;
y is 1 or 2;
and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
It is preferred in some embodiments of the invention that both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen.
Examples of A are phenyl optionally substituted by C1-C6 straight or branched chain alkyl.
Examples of Z are phenyl, e.g. where E is para to the xe2x80x94SO2xe2x80x94 group.
In accordance with some preferred embodiments of the present invention, E and G are independently selected from NH, O and S. In other preferred embodiments of the present invention E is O and G is NH.
In other preferred embodiments Y is C1-C6 straight chain alkyl, and more preferably C2-C3 straight chain alkyl.
In some embodiments of the present invention E and G are independently selected from CH2, NH, O and S and Y is xe2x80x94C1-C4-perfluoroalkyl, or straight chain or branched xe2x80x94C1-C6 alkenyl, xe2x80x94C2-C6-alkenyl, or C2-C6-alkynyl.
In still other embodiments of the present invention, E and G are independently selected from CH2, NH, O and S and Y is straight chain or branched xe2x80x94C1-C6 alkyl.
When G is CH2, in some embodiments of the invention, it is preferred that Y is xe2x80x94C2-C5 -perfluoroalkyl, or straight chain or branched xe2x80x94C1-C6 alkyl,
In still other embodiments of the present invention, E and G are CH2, and Y is straight chain or branched xe2x80x94C1-C6 alkyl, and more preferably Y is straight chain or branched xe2x80x94C1-C5 alkyl.
J is preferably heteroaryl fused to a phenyl and particularly preferred is where J is benzofuranyl, benzothienyl and quinolinyl. J may be indolyl.
When R14 and R15 are on adjacent atoms of J, R14, R15 and J may together preferably form a bicyclic oxygen containing aryl moiety such as benzodioxanyl or benzodioxlyl.
Preferred compounds of the present invention include:
Quinoline-2-carboxylic acid (2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide
Benzofuran-2-carboxylic acid (3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide
Benzofuran-2-carboxylic acid (4-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)methyl-sulfamoyl]-phenoxy}-butyl)-amide
1H-Indole-2-carboxylic acid (3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide
Benzo[b]thiophene-2-carboxylic acid (2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide
N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]propyl}-1,3-benzodioxole-5-carboxamide
N-{4-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]butyl}-1,3-benzodioxole-5-carboxamide
N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}-sulfonyl)phenoxy]propyl}-1-benzothiophene-2-carboxamide
Benzofuran-2-carboxylic acid (2-{4-[benzyl-(2-hydroxycarbamoyl-4,6-dimethyl-phenyl)-sulfamoyl]-phenoxy}-ethyl)-amide.
Halogen, as used herein means fluoro, chloro, bromo and iodo.
Alkyl as used herein means a branched or straight chain radical having from 1 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 1 to 6 carbon atoms also optionally substituted. Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl also optionally substituted as well as perfluoroalkyl.
Alkenyl as used herein means a branched or straight chain radical having from 2 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 2 to 6 carbon atoms, with the chain containing at least one carbon-carbon double bond. Alkenyl, may be used synonymously with the term olefin and includes alkylidenes. Exemplary alkenyl groups include but are not limited to ethylene, propylene and isobutylene.
Alkynyl as used herein means a branched or straight chain radical having from 2 to 20 carbon atoms optionally substituted with one or more groups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, heteroaryl, and more preferably from 3 to 10 carbon atoms, with the chain containing at least one carbon-carbon triple bond.
Alkoxy as used herein means an alkyl-O-group in which the alkyl group is as previously described. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Aryl as used herein refers to phenyl or naphthyl which may be optionally substituted as described above (e.g. R1-4, R-10-13, R14-17 etc.,) such as with one to four substituents selected from the group of alkyl, halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, or heteroaryl.
Heteroaryl, as used herein refers to a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, NH, O and S. Heteroaryl may be optionally substituted with substituents as described above (e.g. R1-4, R10-13, R14-17) such as selected from the group halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido, aryl, and heteroaryl. Heteroaryl includes, but is not limited to pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole.
Cycloalkyl or saturated or unsaturated carbocyclic ring, refers to a cyclic alkyl group having from 3 to 7 carbon atoms and may include from 1 to 2 double bonds. Cycloalkyl groups may be optionally substituted.
Cycloheteroalkyl, as used herein refers to 3 to 7 membered saturated or unsaturated heterocyclic ring having one to three heteroatoms independently selected from N, NH, O, and S and optionally having 1 or 2 double bonds. Cycloheteroalkyl groups may be optionally substituted with from one to three groups. The term heterocycloalkyl or heterocyclic ring includes, but is not limited to oxazolidine, thiazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetramethylene sulfone, dihydropyran, tetrahydropyran, piperidine, pyrrolidine, dioxane, morpholine, azepine and diazepine.
The term xe2x80x9cheteroaryl fused to a phenylxe2x80x9d includes, but is not limited to, benzoxazole, benzoisoxazole, indole, isoindole, benzothiophene, benzofuran, quinoline, quinazoline, quinoxaline, benzotriazole, benzimidazole, benzthiazole, benzopyrazole and isoquinoline. Substitutions may occur on one or both rings.
Pharmaceutical acceptable salts are encompassed by the present invention and include, as appropriate, inorganic and organic salts. Exemplary acid salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Other compounds that are acids can also form salts with alkali metals or alkali earth metals, such as sodium, potassium, calcium, or magnesium, or with organic bases or basic quaternary ammonium salts.
The compounds according to the invention can be in various stereoisomeric forms such as enantiomers or diastereomers. The invention includes optically pure forms of compounds of the present invention prepared in accordance with known methods.
The following compounds (1-10) which may be used in preparing invention compounds are known and references are given hereinbelow. 
Compound 1
a) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr James F.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, Karin R.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.
b) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Kerwin, James F., Jr.; Lebold, Suzanne A.; Lee, Edmund L.; Elmore, Steven W.; et al. Preparation of tricyclic substituted benz[e]isoindoles as a1 adrenergic antagonists. PCT int. Appl WO 9622992 A1 CAN 125:221858.
Compound 2
Troll, Theodor; Schmid, Klaus. Preparation and reactions of a 2H-pyrrolo[3,4-b]pyridine and a 2H-pyrrolo[3,4-b]pyrazine. J. Heterocycl. Chem. (1986), 23(6), 1641-4.
Compound 3
Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr James F.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, Karin R.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.
Compound 4
a) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr James F.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, Karin R.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.
b) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.; Carroll, William A.; Drizin, Irene; Kerwin, James F., Jr.; Lebold, Suzanne A.; Lee, Edmund L.; Elmore, Steven W.; et al. Preparation of tricyclic substituted benz[e]isoindoles as a1 adrenergic antagonists. PCT Int. Appl. WO 9622992 A1 CAN 125:221858.
Compound 5
Geach, Neil; Hawkins, David William; Pearson, Christopher John; Smith, Philip Henry Gaunt; White, Nicolas. Preparation of isoxazoles as herbicides. Eur. Pat. Appl. EP 636622 A1 CAN 122:290845.
Compound 6
Kotovskaya, S. K.; Mokrushina, G. A.; Suetina, T. A.; Chupakhin, O. N.; Zinchenko, E. Ya.; Lesovaya, Z. I.; Mezentsev, A. S.; Chernyshov, A. I.; Samoilova, L. N. Benzimidazolyl derivatives of penicillin and cephalosporin: synthesis and antimicrobial activity. Khim.-Farm. Zh. (1989), 23(8), 952-6.
Compound 7
Wagner, Klaus. Bactericidal and fungicidal 4-chlorobenzothiazoles. Ger. Offen. DE 2136924 CAN 78:111293.
Compound 8
Eggensperger, Heinz; Diehl, Karl H.; Kloss, Wilfried. 2-Hydroxy-4-alkoxybenzophenones. Ger. DE 1768599 711223. CAN 76:85557.
Compound 9
Lichtenthaler, Frieder W.; Moser, Alfred. Nucleosides. 44. Benzo-separated pyrazolopyrimidines: expeditious syntheses of [3,4-g]- and [3,4-h]-linked pyrazoloquinazolinones. Tetrahedron Lett. (1981), 22(44), 4397-400.
Compound 10
Terpstra, Jan W.; Van Leusen, Albert M. A new synthesis of benzo[b]thiophenes and benzo[c]thiophenes by annulation of disubstituted thiophenes. J. Org. Chem. (1986), 51(2), 230-8.
The invention compounds may be prepared using conventional techniques known to those skilled in the art of organic synthesis.
Accordingly this invention provides a process for preparing a compound of Formula I as defined above which comprises one of the following:
a) reacting a compound of formula II: 
wherein J, L, G, Y, E, Z, A and R7 are defined above or a reactive derivative thereof, with a compound of formula III:
NH2OHxe2x80x83xe2x80x83(III)
to give a corresponding compound of formula I;
b) resolving a mixture (e.g. racemate) of optically active isomers of a compound of formula I to isolate one enantiomer or diastereomer substantially free of the other enantiomer or diastereomers;
c) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt.
Means of coupling the carboxylic acid moiety to hydroxylamine are well known to those skilled in the art.
The following schemes (Scheme I and II) illustrates the general reaction sequence employed. For purposes of illustration only, wherein the group A is a phenyl, methyl anthranilate is reacted with p-fluorobenzenesulfonyl chloride to provide the requisite N-aryl sulfonamido-ester which is then alkylated to provide the N,N-disubstituted sulfonamide. This compound can then be converted into the elongated sulfonamide by two routes. The N,N-disubstituted sulfonamide ester may be hydrolyzed to the carboxylic acid and then subjected to a nucleophilic displacement of the fluoro substituent, or it can be treated directly with a suitable nucleophile and subsequently hydrolyzed to the acid. The acid may then be converted into the corresponding hydroxamic acid. 
Scheme II depicts the preparation of suitable nucleophiles (for when E and G are independently N, O, or S and L is xe2x80x94C(O)xe2x80x94 or S(O)x) employed in the displacement of the aryl fluoride. 
Alternatively, other nucleophiles for use in the displacement reaction (G is C) can be prepared via the route in Scheme III. A suitable ester is condensed with a lactone to provide a xcex2-ketolactone. This lactone is then ring opened with concomitant decarboxylation to provide the requisite nucleophile for use in the displacement reaction. 
Alternatively, other compounds of the invention can be prepared via the route shown in Scheme 4. For purposes of illustration only, wherein the group A is shown as a phenyl, methyl anthranilate is reacted with p-bromobenzenesulfonyl chloride to provide the requisite N-aryl sulfonamido-ester which is then alkylated to provide the N,N-disubstituted sulfonamide. This compound can then be converted into the elongated sulfonamide by two routes. The N,N-disubstituted sulfonamide ester may be hydrolyzed to the carboxylic acid and then subjected to a palladium catalyzed coupling to a suitable alkyl boron reagent (compound A, prepared via the route depicted in Scheme 5), or it can be treated directly with a suitable alkyl boron reagent and subsequently hydrolyzed to the acid. The acid may then be converted into the corresponding hydroxamic acid. 
Compound A (where L is xe2x80x94C(O)xe2x80x94) may be prepared via the following route. A precursor carboxylic acid is converted to the Weinreb amide via formation of the acid chloride and subsequent displacement with methoxymethyl amine. The amide is then treated with a grignard reagent, the olefin of which is subsequently hydroborated with 9-BBN for use in the palladium coupling reaction. 
In another aspect of the present invention, the invention includes a method of treating a pathological condition or disorder mediated by matrix metalloproteinases in mammals which comprises providing to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound.
In preferred embodiments of the invention, compounds of the present invention are particularly useful for the treatment of rheumatoid arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease and HIV infection.
Compounds of this invention may be provided to a patient in need thereof. They may be administered neat or with a pharmaceutical carrier to the patient or provided in the form of a pro-drug which will be converted by the patient. The pharmaceutical carrier may be solid or liquid and generally may be any pharmaceutically acceptable carrier. Formulation of drugs is discussed, for example, in Hoover, J. E., Remington ""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 1975.
Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The dosage to be used in the treatment of a specific patient suffering from a disease or condition in which MMPs and TACE are involved must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The following specific examples are included for illustrative purposes and are not to be construed as limiting to this disclosure in any way. Other procedures useful for the preparation of the compounds of this invention will be apparent to those skilled in the art of synthetic organic chemistry.